Abstract

The dynamics of CD4(+) T cell memory development remain to be examined at genome scale. In malaria-endemic regions, anti-malarial chemoprevention protects long after its cessation and associates with effects on CD4(+) T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T(H)1) and follicular helper T (T-FH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T(H)1 and T-FH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T-FH and central memory were revealed, with antimalarials modulating these responses and boosting T(H)1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4(+) T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/).

Authors	Soon, Megan S. F.; Lee, Hyun Jae; Engel, Jessica A.; Straube, Jasmin; Thomas, Bryce S.; Pernold, Clara P. S.; Clarke, Lachlan S.; Laohamonthonkul, Pawat; Haldar, Rohit N.; Williams, Cameron G.; Lansink, Lianne I. M.; Moreira, Marcela L.; Bramhall, Michael; Koufariotis, Lambros T.; Wood, Scott; Chen, Xi; James, Kylie R.; Lonnberg, Tapio; Lane, Steven W.; Belz, Gabrielle T.; Engwerda, Christian R.; Khoury, David S.; Davenport, Miles P.; Svensson, Valentine; Teichmann, Sarah A.; Haque, Ashraful
Journal	NATURE IMMUNOLOGY
Pages	1597-1610
Volume	21
Date	1/10/2020
Grant ID	1126399
Funding Body	Australian National Health & Medical Research Council
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41590-020-0800-8